This Program Project proposes an integrated investigation of molecular genetic, biochemical, serological and functional aspects of the human major histocompatibility complex (HLA) and HLA antigen interactions with T- lymphocytes. The overall objective is to obtain a better understanding of the function of the HLA genes and their gene products. This includes the analysis of regulation of HLA gene expression and function of the HLA antigens particularly as they relate to T-lymphocyte activation and generation of helper T cells and cytotoxic T-cells. This program aims at gaining basic information about allograft reactions and to obtain a better understanding of the underlying mechanisms for the relationship between HLA gene products, and T-cells, B cells and antigen presenting cells. The program is composed of one Core Component for common reagents and administrative Resources and five projects. The five projects are entitled: (1) T Lymphocyte Activation by Alloantigens. (3) Factors Controlling HLA Class I Expression. (4) Genes controlling HLA Class II Expression in Lymphocytes. (5) Regulation and Function of Human CD4. We will in the first project investigate the different requirements for primary alloantigen activation of T-cells, in contrast to the requirements for secondary alloantigen activation. The involvement of CD2, CD45 and CD28 on the T-cells during alloactivation in vitro is the major aim of the study. The basic question of restriction of murine T-cells to transgenic xeno MHC and peripheral tolerance will be investigated in the second project. This will be investigated using HLA transgenic mice. The third and fourth projects involve investigations of gene regulation of HLA class I and HLA class II respectively. The fifth project concerns the investigation of regulation and function of CD4 during T-cell maturation in the thymus. This program aims at gaining basic information about allograft reactions and to obtain a better understanding of the underlying mechanisms for the relationshipH48789 36of social cognition.